The primary objectives of this proposal include: a) To evaluate the induction and reversal of organic nitrate tolerance (in vitro and in vivo); b) to determine the mechanism of tolerance development to organic nitrates as well as other vasodepressor agents; c) to investigate the mechanism by which organic nitrates and other direct acting spasmolytic compounds relax smooth muscle; and d) to synthesize and test nitrate high affinity analogs designed to react with and bind to nitrate receptors.